Chronic hepatitis C is a leading cause of morbidity and mortality in veterans. Current treatment options have only limited efficacy in veterans and are poorly tolerated. Herpes simplex type 2 virus co-infection commonly occurs in veterans with hepatitis C but is poorly studied. In patients with HIV, treatment of herpes simplex type 2 with well-tolerated oral drugs improves outcomes. We propose to study similar interactions of herpes simplex type 2 in hepatitis C. We also will begin preliminary studies to examine potential interactions of HSV-1 infection in HCV. Because of the varying performance of screening assays for HSV-2, our first aim is to validate a two-step approach for confirming herpes simplex type 2 infection in veterans with HCV. This will allow us to identify accurately persons with HSV-2/HCV infection AND study the effects of HSV-2 on HCV. In aim 2, we will perform a randomized, double-blind, placebo-controlled clinical trial evaluating the effect of HSV-2 suppression on HCV viral load in patients with genotype 1 hepatitis C virus and herpes simplex type-2 co-infection. In aim 3, we will examine the effects of HSV-1 suppression on serum hepatitis C viral load in herpes simplex type-1/hepatitis C virus co-infected veterans without evidence of herpes simplex type 2 infection. The VA is the largest single provider of care for persons with hepatitis C in the United States, but the majority of hepatitis C infected veterans are unable to receive or benefit from currently available therapies. This proposal examines a novel approach to delaying hepatitis C progression by suppressing herpes simplex viruses. Evaluating this approach could lead to improved, well-tolerated therapies for HCV in difficult-to-treat populations.